Why Can't We Prevent Alzheimer's?

Familial Alzheimer’s is transferred to offspring such that each child has a 50 percent chance of inheritance if one parent has it. How many of us are walking around with these loaded guns? The information is seductive. Many of us want to peek at our genomes. Is there information in there that could tell us we are smarter, or in more danger, than we think? Yet, a firestorm erupted in recent weeks as the FDA temporarily suspended 23andMe’s genetic testing services over concerns about the reliability of their tests. One reason for the concern was that there was a single approval process for hundreds of disease markers tested. But another was that families may carry a multitude of rare mutations, but taken out of the genetic context of that family, a single mutation may not predict a disease, Sherman Elias, a clinical geneticist and professor emeritus at Northwestern University, told me.

A decade ago, “genome-wide association studies” emerged as a tool to examine large datasets, sometimes up to 50,000 people, in order to identify gene variants that cause common diseases. The studies were based on the premise that any common disease must have common genetic drivers. In some cases, it turned out to be true. Recent large-scale studies on late-onset Alzheimer’s have pointed to 22 “areas of interest,” including mutations in a gene called BIN1 on chromosome 2 and CLU on chromosome 8, each which have a role in sweeping out old proteins from the attics of our brains. And yet, a decade after the first draft of the human genome was released, at a cost of $3 billion dollars, the public is clamoring for more of its secrets, and a means to treat disease. Where are all of the drugs?

Alzheimer’s is so common, shouldn’t we have a drug? In fact, many common diseases are turning out to have diverse and collective genetic origins, or etiologies. Consider that the human genome contains 23,000 protein coding genes. Many experts had expected it would carry 100,000 genes. The initial reaction to this finding was that the genome was surprisingly simple. How wrong we were. We now know that the genome contains heaps of code that is transcribed into RNA but never becomes protein, the so-called non-coding RNA. (The group ENCODE recently reported 75 percent of the genome is published into RNA while only about 2 percent codes a protein). Some of it, called lincRNA, is very long. Call it the Dark Matter of the Genome, if you like, because for the most part, we don’t know how it works.

In my day job, I investigate the role of RNA in Alzheimer’s disease. I work on computer problems. One of these problems is how RNA is processed in Alzheimer’s brains. RNA is tailored by seamstresses in our cells, leading to many species or “isoforms” of RNA and protein. I like to think of these isoforms as tiny dresses. A single gene can be patterned to build many styles of a dress. And some RNA can regulate other RNA, tuning its expression “up” or “down,” deciding how many dresses are made. Furthermore, a series of “epigenetic” molecules attaches to the structure of the genome and switch genes “on” or “off.” Thus, our genes are regulated by disparate forces, which decide when, which, and how many of these dresses are sewn in the cellular factory.

Alzheimer’s research is undergoing a shift to a “systems” or “networks” approach, where instead of just pinpointing a single mutation or genetic variant, we are now looking at networks—groups of molecules that go to work together on shifts on the cellular factory floor. We can see major shifts in RNA occurring in brain tissue, but the causes of these changes are often invisible to us. So far, a large component of it appears to us as Dark Matter.

The Small Species Camp

Alzheimer’s disease has, for decades, been dominated by the “amyloid cascade hypothesis,” the theory that large plaques of amyloid-beta (building up outside cells) and tau proteins (building up inside cells) starve and kill neurons.

Yet one emerging theory suggests that it’s the smaller forms of amyloid-beta molecules that cause all of the trouble. William L. Klein, a neurobiologist at the Cognitive Neurology and Alzheimer’s Disease Center at Northwestern University, is among the scientists credited with originating this “small species camp,” more technically known as the “Abeta oligomer cascade hypothesis.” His claim: A smaller form of amyloid beta, or “oligomer,” acts as a neurotoxin, adhering to cell receptors and jamming communication. Klein’s team found that they bind to a spot near a receptor in the hippocampus called NMDA, which has long been implicated in the creation of new long-term memories.

The NMDA receptor works like a tiny gate that opens and closes and lets ion signals jump from cell to cell. The toxins were binding to a spot near the receptor and keeping the gates jammed open (a “gain-of-function” disorder) disrupting proper cell-to-cell communication, and along with it the creation of new synapses, the ability to make new memories, and what neuroscientists call “plasticity.” In fact, the Federal Drug Administration approved an NMDA receptor inhibitor called Memantine in 2003 as a treatment for moderate to severe Alzheimer’s disease, but scientists were without good explanation for why it had modest benefits.

Presented by

Jim Kozubek is a science writer and computational biologist based in Cambridge, Massachusetts.

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